Dr Garrido-Laguna on the Mechanism of Action of RMC-6236 in KRAS-Mutant PDAC

Ignacio Garrido-Laguna, MD, PhD, MBA, professor, oncology, director, Phase 1 Program, co-leader, GI Oncology Multidisciplinary Disease Group, University of Utah School of Medicine, discusses preliminary safety and efficacy data with the use of RMC-6236 in patients with KRAS-mutated pancreatic ductal adenocarcinoma (PDAC), highlighting the ongoing investigation of this agent.

Findings from the phase 1 RMC-6236-001 trial (NCT05379985) were presented at the 2023 ESMO Congress. In this trial, patients with PDAC and non–small cell lung cancer (NSCLC) harboring KRAS G12X mutations, except for KRAS G12C, received monotherapy treatment with the RAS inhibitor RMC-6236.

RMC-6236 has a novel mechanism of action, as it is a molecular glue that binds together 2 proteins, cyclophilin A and KRAS, which do not typically interact with one another, Garrido-Laguna says. The binding of these proteins creates a steric occlusion that prevents the binding of downstream effector proteins in the KRAS pathway, Garrido-Laguna explains. No available drugs for patients with PDAC have this mechanism of action, Garrido-Laguna notes.

Thus far, the RMC-6236-001 trial enrolled 65 patients with metastatic PDAC treated with at least 80mg of RMC-6236 per day. Most patients were heavily pretreated and had received a median of 3 prior lines of therapy (range, 1-7). Of these patients, 46 patients with PDAC who initiated treatment with RMC-6236 at least 8 weeks prior to data extract date experienced an overall response rate of 20%, and 27 patients were still receiving the study treatment at the data cutoff date. The median time to response was 1.4 months (range, 1.2-4.1), and the median time on treatment was 3.3 months (range, 0.2-10.9).

This investigation has shown that RMC-6236 has a tolerable safety profile, and most of the observed toxicities have been grade 1/2, Garrido-Laguna emphasizes. The most common toxicities seen with this agent in the pooled PDAC and NSCLC populations treated with at least 80mg of RMC-6236 per day (n = 111) were rash, nausea, and diarrhea. The nausea was manageable and tended to improve over time, Garrido-Laguna notes. Grades 1, 2, and 3 rash occurred in 52%, 23%, and 6% of patients, respectively. Conversely, cetuximab (Erbitux), an EGFR inhibitor that is approved for patients with metastatic colorectal cancer, is associated with an approximate 60% incidence of grade 2/3 rash, even with preemptive prophylactic treatment, according to Garrido-Laguna. Although RMC-6236 is associated with a high incidence of rash at higher dose levels, many patients in the trial who received the agent at dose levels up to 300 mg did not experience rash, Garrido-Laguna concludes.